We are studying how collagen cross-links have evolved to adapt human bone, cartilage and other supporting tissues for their distinctive functions. We have raised the structure which predicts a novel chemistry and critical role for pyrrole cross-links in bone collagen and identified a previously unknown cross-link, arginoline, in cartilage collagen. We propose and will seek to validate a unified theory of oxidative maturation for cross-links in the fibrillar collagens of all tissues. Though the lysyl oxidase cross-linking mechanism was discovered in the 1970s, much is still unknown. Post-translational differences in collagen quality between individuals, notably in the cross-linking chemistry of bone and cartilages, are potential risk factors for osteoporotic fracture and joint failure. They result from cumulative environmental influences rather than a direct genetic basis. We are pursuing this through analyses of bone, cartilage and other skeletal tissue collagens using advanced mass spectrometric protein techniques. The clinical significance is the promise of new molecular targets in the effort to meet the public health challenges of osteoporosis and osteoarthritis. Skeletal tissues depend heavily on the cross-linking of highly specialized collagens for their unique strengths, properties and longevity. The translational aim, therefore, is to seek new molecular targets for therapy and non- invasive biomarkers based on urinary collagen peptides that can index a patient's bone quality, joint cartilage breakdown rate and other measures of skeletal health.